International Journal of Gynecological Cancer, 2015
Polymerase epsilon (POLE) is a DNA polymerase with a proofreading (exonuclease) domain, responsib... more Polymerase epsilon (POLE) is a DNA polymerase with a proofreading (exonuclease) domain, responsible for the recognition and excision of mispaired bases, thereby allowing high-fidelity DNA replication to occur. The Cancer Genome Atlas research network recently identified an ultramutated group of endometrial carcinomas, characterized by mutations in POLE, and exceptionally high substitution mutation rates. These POLE mutated endometrial tumors were almost exclusively of the endometrioid histotype. The prevalence and patterns of POLE mutated tumors in endometrioid carcinomas of the ovary, however, have not been studied in detail. In this study, we investigate the frequency of POLE exonuclease domain mutations in a series of 89 ovarian endometrioid carcinomas. We found POLE mutations in 4 of 89 (4.5%) cases, occurring in 3 of 23 (13%) International Federation of Gynecology and Obstetrics (FIGO) grade 1, 1 of 43 (2%) FIGO grade 2, and 0 of 23 (0%) FIGO grade 3 tumors. All mutations were somatic missense point mutations, occurring at the commonly reported hotspots, P286R and V411L. All 3 POLE-mutated FIGO grade 1 tumors displayed prototypical histology, and the POLE-mutated FIGO grade 2 tumor displayed morphologic heterogeneity with focally high-grade features. All 4 patients with POLE-mutated tumors followed an uneventful clinical course with no disease recurrence; however, this finding was not statistically significant (P = 0.59). The low rate of POLE mutations in ovarian endometrioid carcinoma and their predominance within the low FIGO grade tumors are in contrast to the findings in the endometrium.
Methods in molecular biology (Clifton, N.J.), Jan 31, 2015
Morpholino oligonucleotides (MO) are an innovative tool that provides a means for examining and m... more Morpholino oligonucleotides (MO) are an innovative tool that provides a means for examining and modifying gene expression outcomes by antisense interaction with targeted RNA transcripts. The site-specific nature of their binding facilitates focused modulation to alter splice variant expression patterns. Here we describe the steric-blocking of human telomerase reverse transcriptase (hTERT) Δα and Δβ splice variants using MO to examine cellular outcomes related to pluripotency and differentiation in human embryonic stem cells.
Placentation is critical for establishing a healthy pregnancy. Trophoblasts mediate implantation ... more Placentation is critical for establishing a healthy pregnancy. Trophoblasts mediate implantation and placentation and certain subtypes, most notably extravillous cytotrophoblast, are highly invasive. Trophoblast invasion is tightly regulated by microenvironmental cues that dictate placental morphology and depth. In choriocarcinomas, malignant trophoblast cells become hyperinvasive, breaching the myometrium and leading to major complications. Nodal, a member of the TGF-β superfamily, is expressed throughout the endometrium during the peri-implantation period and in invasive trophoblast cells. Nodal promotes the invasion of numerous types of cancer cells. However, Nodal's role in trophoblast and choriocarcinoma cell invasion is unclear. Here we show that Nodal stimulates the invasion of both the non-malignant HTR-8SV/neo trophoblast and JAR choriocarcinoma cells in a dose-dependent manner. We found that endogenous β-arrestins and Ral GTPases, key regulators of the cell cytoskeleto...
Breast carcinoma cells and embryonic progenitors similarly implement stem cell-associated signali... more Breast carcinoma cells and embryonic progenitors similarly implement stem cell-associated signaling pathways to sustain continued growth and plasticity. Indeed, recent studies have implicated signaling pathways, including those associated with the Notch, and Transforming Growth Factor-Beta (TGF-beta) superfamilies, as instrumental to both embryological development and breast cancer progression. In particular, Nodal, an embryonic morphogen belonging to the TGF-beta superfamily, and its co-receptor, Cripto-1, are requisite to both embryogenesis and mammary gland maturation. Moreover, these developmental proteins have been shown to promote breast cancer progression. Here, we review the role of Nodal and its co-receptor Cripto-1 during development and we describe how this signaling pathway may be involved in breast cancer tumorigenesis. Moreover, we emphasize the potential utility of this signaling pathway as a novel target for the treatment and diagnosis of breast cancer.
International Journal of Gynecological Cancer, 2015
Polymerase epsilon (POLE) is a DNA polymerase with a proofreading (exonuclease) domain, responsib... more Polymerase epsilon (POLE) is a DNA polymerase with a proofreading (exonuclease) domain, responsible for the recognition and excision of mispaired bases, thereby allowing high-fidelity DNA replication to occur. The Cancer Genome Atlas research network recently identified an ultramutated group of endometrial carcinomas, characterized by mutations in POLE, and exceptionally high substitution mutation rates. These POLE mutated endometrial tumors were almost exclusively of the endometrioid histotype. The prevalence and patterns of POLE mutated tumors in endometrioid carcinomas of the ovary, however, have not been studied in detail. In this study, we investigate the frequency of POLE exonuclease domain mutations in a series of 89 ovarian endometrioid carcinomas. We found POLE mutations in 4 of 89 (4.5%) cases, occurring in 3 of 23 (13%) International Federation of Gynecology and Obstetrics (FIGO) grade 1, 1 of 43 (2%) FIGO grade 2, and 0 of 23 (0%) FIGO grade 3 tumors. All mutations were somatic missense point mutations, occurring at the commonly reported hotspots, P286R and V411L. All 3 POLE-mutated FIGO grade 1 tumors displayed prototypical histology, and the POLE-mutated FIGO grade 2 tumor displayed morphologic heterogeneity with focally high-grade features. All 4 patients with POLE-mutated tumors followed an uneventful clinical course with no disease recurrence; however, this finding was not statistically significant (P = 0.59). The low rate of POLE mutations in ovarian endometrioid carcinoma and their predominance within the low FIGO grade tumors are in contrast to the findings in the endometrium.
Methods in molecular biology (Clifton, N.J.), Jan 31, 2015
Morpholino oligonucleotides (MO) are an innovative tool that provides a means for examining and m... more Morpholino oligonucleotides (MO) are an innovative tool that provides a means for examining and modifying gene expression outcomes by antisense interaction with targeted RNA transcripts. The site-specific nature of their binding facilitates focused modulation to alter splice variant expression patterns. Here we describe the steric-blocking of human telomerase reverse transcriptase (hTERT) Δα and Δβ splice variants using MO to examine cellular outcomes related to pluripotency and differentiation in human embryonic stem cells.
Placentation is critical for establishing a healthy pregnancy. Trophoblasts mediate implantation ... more Placentation is critical for establishing a healthy pregnancy. Trophoblasts mediate implantation and placentation and certain subtypes, most notably extravillous cytotrophoblast, are highly invasive. Trophoblast invasion is tightly regulated by microenvironmental cues that dictate placental morphology and depth. In choriocarcinomas, malignant trophoblast cells become hyperinvasive, breaching the myometrium and leading to major complications. Nodal, a member of the TGF-β superfamily, is expressed throughout the endometrium during the peri-implantation period and in invasive trophoblast cells. Nodal promotes the invasion of numerous types of cancer cells. However, Nodal's role in trophoblast and choriocarcinoma cell invasion is unclear. Here we show that Nodal stimulates the invasion of both the non-malignant HTR-8SV/neo trophoblast and JAR choriocarcinoma cells in a dose-dependent manner. We found that endogenous β-arrestins and Ral GTPases, key regulators of the cell cytoskeleto...
Breast carcinoma cells and embryonic progenitors similarly implement stem cell-associated signali... more Breast carcinoma cells and embryonic progenitors similarly implement stem cell-associated signaling pathways to sustain continued growth and plasticity. Indeed, recent studies have implicated signaling pathways, including those associated with the Notch, and Transforming Growth Factor-Beta (TGF-beta) superfamilies, as instrumental to both embryological development and breast cancer progression. In particular, Nodal, an embryonic morphogen belonging to the TGF-beta superfamily, and its co-receptor, Cripto-1, are requisite to both embryogenesis and mammary gland maturation. Moreover, these developmental proteins have been shown to promote breast cancer progression. Here, we review the role of Nodal and its co-receptor Cripto-1 during development and we describe how this signaling pathway may be involved in breast cancer tumorigenesis. Moreover, we emphasize the potential utility of this signaling pathway as a novel target for the treatment and diagnosis of breast cancer.
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